Alpha-cell re-generation combined with conversion to beta cells

Abstract

The present invention relates to methods of generating a population of beta cells from a population of alpha cells, by contacting said population of alpha cells with GABA or a GABA receptor agonist, in combination with a monoclonal glucagon neutralizing antibody or other alpha cell mass regulating compounds, for an improved diabetes therapy.

The invention claimed is: 
     
       1. A method for producing a population of pancreatic beta cells comprising the step of contacting a population of alpha cells with (a) GABA or a GABA receptor agonist in combination with (b) a glucagon neutralizing monoclonal antibody, selected from GLU001 or a humanized version thereof, or a glucagon receptor antagonist;
 wherein said glucagon neutralizing monoclonal antibody binds glucagon and said glucagon receptor antagonist binds a glucagon receptor; and 
 wherein glucagon receptor signaling is decreased or inhibited. 
 
     
     
       2. The method of  claim 1 , wherein the glucagon neutralizing monoclonal antibody binds to glucagon. 
     
     
       3. The method of  claim 1 , wherein said glucagon neutralizing monoclonal antibody is GLU001. 
     
     
       4. The method of  claim 1 , wherein glucagon neutralizing monoclonal antibody competes with GLU001 for binding to glucagon. 
     
     
       5. The method of  claim 1 , wherein glucagon neutralizing monoclonal antibody binds to same epitope as GLU001. 
     
     
       6. The method of  claim 1 , wherein the glucagon receptor antagonist is an anti-glucagon receptor antibody. 
     
     
       7. A pharmaceutical composition comprising (a) GABA or a GABA receptor agonist in combination with (b) a glucagon neutralizing monoclonal antibody, selected from GLU001 or a humanized version thereof, or a glucagon receptor antagonist;
 wherein said glucagon neutralizing monoclonal antibody binds glucagon and said glucagon receptor antagonist binds a glucagon receptor; and 
 wherein glucagon receptor signaling is decreased or inhibited. 
 
     
     
       8. A method of treating diabetes in a patient in need thereof comprising a step of administering to said patient an effective amount of a combination of (a) GABA or a GABA receptor agonist with (b) a glucagon neutralizing monoclonal antibody, selected from GLU001 or a humanized version thereof, or a glucagon receptor antagonist;
 wherein said glucagon neutralizing monoclonal antibody binds glucagon and said glucagon receptor antagonist binds a glucagon receptor; and 
 wherein glucagon receptor signaling is decreased or inhibited. 
 
     
     
       9. The method of  claim 8 , wherein the diabetes is type 1 diabetes. 
     
     
       10. The method of  claim 8 , wherein the diabetes is type 2 diabetes. 
     
     
       11. A method for increasing beta cells mass in a patient in need thereof comprising a step of administering to said patient an effective amount of a combination of (a) GABA or a GABA receptor agonist with (b) a glucagon neutralizing monoclonal antibody, selected from GLU001 or a humanized version thereof, or a glucagon receptor antagonist;
 wherein said glucagon neutralizing monoclonal antibody binds glucagon and said glucagon receptor antagonist binds a glucagon receptor; and 
 wherein glucagon receptor signaling is decreased or inhibited.